Selective autophagy in Parkinson'sdisease

帕金森病的选择性自噬

基本信息

批准号：
9917855
负责人：
Ai Yamamoto
金额：
$ 48.97万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917855
关键词：
Adaptor Signaling Protein Adult Affect Autophagocytosis Autophagosome Axon Biochemistry Brain Catabolic Process Cells Consumption Data Degradation Pathway Development Disease Event Functional disorder Genes Genetic Models Health In Vitro Invertebrates Lead Lysosomes Masks Mediating Membrane Methods Mind Mitochondria Modeling Mus Neurologic Neurons Outcome PINK1 gene Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Phenotype Play Predisposition Proteins Rattus Resources Role Rotenone Series Starvation System Therapeutic Toxin Transgenic Model Vesicle aging brain alpha synuclein axonopathy base dopaminergic neuron experimental study human disease in vivo macromolecule mouse genetics mouse model neuron loss parkin gene/protein protein aggregation protein degradation protein misfolding response scaffold stressor synucleinopathy therapeutic target treatment strategy

项目摘要

In Parkinson's disease (PD), not only has macroautophagy been proposed to be a potential therapeutic target, but its dysfunction has also been implicated in disease pathogenesis both indirectly and directly. Macroautophagy (MA) is a lysosome-mediated degradation pathway that first sequesters cytosolic constituents into a transient, multimembranous vesicle known as an autophagosome (AP), and then fuses into the endolysosomal system for degradation. Although classically known to promote bulk degradation in response to starvation, MA also promotes the selective turnover of defined substrates in response to different stressors, such as protein misfolding and mitochondrial damage. These selective MA pathways achieve selectivity using adaptor proteins which scaffold cargo to the core autophagic machinery and the nascent AP membrane. Two selective autophagy pathways have been particularly relevant in PD; aggrephagy, the selective degradation of protein aggregates, and mitophagy, the selective degradation of mitochondria. If selective MA pathways are to be considered in global therapeutic strategies for the treatment of PD, it is essential that we apply these questions to the mammalian brain and models of PD. With this in mind, we will use newly created mouse models and methods to examine and validate mechanistically the relevance of these two pathways on pathogenesis in mouse models of genetics PD. First, building upon our identification of the selectivity adaptor for aggrephagy, we will establish the mechanism by which α-synuclein oligomers enter aggrephagy and whether affecting its degradation might influence the phenotype, with a special emphasis on axonal pathology, in a series of transgenic models of α-synuclein. Next, building upon our findings that mitochondrial are by far the most prevalent autophagic cargo in the brain, we will examine the mechanism by which PINK1 and Parkin might exert their function in the brain. First, we will establish if compensatory changes in macroautophagic pathways might be responsible for masking the constitutive loss of PINK1 or Parkin in vivo, then use mouse genetics to establish better the relationship between these two PD genes and selective macroautophagy.

在帕金森氏病（PD）中，不仅提出了大型自噬是一种潜在的疗法靶标，但其功能障碍在疾病发病机理中也隐含了间接和直接的疾病发病机理。大量噬菌体（MA）是一种溶酶体介导的降解途径，首先隔离胞质构成变成瞬态的多膜囊泡，称为自噬体（AP），然后融合到降解的内溶性系统。尽管经典已知是为了促进散装降解的响应 MA饥饿，MA还促进了针对不同压力源的选择性转移，例如蛋白质错误折叠和线粒体损伤。这些选择性的MA途径使用辅助蛋白，可支撑货物到核心自噬机械和新生AP膜。二选择性自噬途径在PD中特别相关。敏锐的，选择性降解的蛋白质聚集体和线粒体，线粒体的选择性降解。如果选择性的MA途径是在全球治疗PD治疗策略中都需要考虑，我们必须应用这些治疗向哺乳动物大脑和PD模型的问题。考虑到这一点，我们将使用新创建的鼠标机械检查和验证这两种途径的模型和方法遗传学小鼠模型PD的发病机理。首先，基于我们对选择性适配器的识别对于Acrophagy，我们将建立α-阴性核蛋白低聚物的机制影响其降解是否可能影响表型，特别强调轴突病理，在一系列α-突触核蛋白的转基因模型中。接下来，基于我们的发现线粒体是迄今为止我们将是大脑中最普遍的自噬货物，我们将检查Pink1和Parkin的机制可能会在大脑中发挥其功能。首先，我们将确定大型自噬的补偿性变化是否途径可能是掩盖pink1或parkin in Vivo的构成损失的原因，然后使用鼠标仿制药可以更好地建立这两个PD基因与选择性大型噬菌体之间的关系。